Keratoconus
Keratoconus (Rabinowitz, 1998; Krachmer et al., 1994; Bron, 1988) is the most common corneal dystrophy, affecting 1 in 2000 persons. Keratoconus results in corneal thinning and is named for the conical shape that the cornea develops. The progressive distortion of corneal shape usually becomes noticeable in early adulthood, causing increasingly severe astigmatism, myopia, and higher-order aberrations that become difficult to correct by spectacles or contact lenses. When distortions reach the point that refractive correction is no longer possible, corneal transplant is the only option.
Methods to strengthen the cornea and prevent progression of the disease are needed. There is evidence that crosslinking of corneal collagen that occurs in diabetes provides protection against keratoconus (Seiler et al., 2000) Additionally, groups have reported strengthening of the cornea through common crosslinking agents. Glyceraldehyde has been used as a corneal crosslinking agent, but it has significant toxicity. An approach to minimize toxicity of the drug itself uses topically applied riboflavin, which is then subjected to ultraviolet light (Tae et al., 2000; Tessier et al., 2002; Spoerl and Seiler, 1999; Spoerl et al., 1997; Wollensak et al., 2003) Longitudinal studies over 3 years or more have shown that treating the cornea with UV activated crosslinking can provide sufficient structural reinforcement to slow or halt the progression of keratoconus (Wollensak et al., 2003; Wollensak, 2006). While uv-activated riboflavin represents a possible advance in the treatment of keratoconus, it would be optimal to overcome the limitations of this treatment. Riboflavin/UV requires painful removal of the epithelium with risk of long-term ulceration; it uses UV light, with inherent risk of damage to ocular tissues; it requires 30 minutes of irradiation which is clinically undesirable and increases the risk of corneal infection. Therefore, clinically, there is a need for a treatment that prevents disease progression and remedies the shortcomings of uv-activated riboflavin treatment. In particular, there is a need in the art of ocular medicine for one or more of the following: 1) improved drug; 2) improved administration of drug; and 3) improved irradiation protocol.
Myopia
Myopia affects 30% of the population in the U.S. and Europe, and 70-90% of the population in some Asian countries (Lin L L, Shih Y F, Hsiao C K, Chen C J, Lee L A, Hung P T. Epidemiologic study of the prevalence and severity of myopia among schoolchildren in Taiwan in 2000. J Formos Med. Assoc. 2001; 100(10):684-91; Chow, Y. C., Dhillon, B. B., Chew, P. T. & Chew, S. J. Refractive errors in Singapore medical students. Singapore Medical Journal 45, 470-474 (1990); Wong, T. Y., Foster, P. J., Hee, J. J., Ng, T. P., Tielsch, J. M., Chew, S. J., Johnson, G. J. & Seah, S. K. Prevalence and risk factors for refractive errors in adult Chinese in Singapore. Investigative Ophthalmology & Visual Science 41, 2486-2494 (2000)). High myopia of greater than 8 diopters affects 0.2-0.4% of the US population and up to 1% of the population in Asian countries (Sperduto, R. D., Seigel, D. D., Roberts, J. J. & Rowland, M. M. Prevalence of myopia in the United States. 405-407 (1983); Tokoro, T. On the definition of pathologic myopia in group studies. Acta Opthalmol Suppl 185, 107-108 (1998)). Indeed, degenerative myopia is the leading cause of untreatable blindness in China, Taiwan, and Japan, and is ranked 7th in the United States (Xu L, Wang Y, Li Y, Wang Y, Cui T, Li J, Jonas J B. Causes of blindness and visual impairment in urban and rural areas in Beijing: the Beijing Eye Study. Ophthalmology. 2006 113:1134.e1-11; Hsu W M, Cheng C Y, Liu J H, Tsai S Y, Chou P. Prevalence and causes of visual impairment in an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology. 2004; 111(1):62-9; Iwase A, Araie M, Tomidokoro A, Yamamoto T, Shimizu H, Kitazawa Y; Tajimi Study Group. Prevalence and causes of low vision and blindness in a Japanese adult population: the Tajimi Study. Ophthalmology. 2006; 113(8):1354-62; Curtin, B. J. The myopias: basic science and clinical management (Lippincott Williams & Wilkins, 1985).
In degenerative myopia there is progressive axial elongation of the eye. The excessive axial enlargement in degenerative myopia causes stretching and thinning of the ocular coats (sclera and chorioretinal tissues). Because this stretching and thinning occurs preferentially in the posterior pole and involves the macula, eyes with degenerative myopia are subject to visual loss. The causes of scleral thinning and stretching in degenerative myopia are incompletely understood, but enhanced turnover of scleral collagen and alteration of scleral glycosaminoglycans are contributory in the disease. As the mechanical properties of the sclera are altered in myopia, the eye is prone to stretching due to the load effect of intraocular pressure. When the sclera stretches in pathologic myopia, the adjacent retina and choroid are also stretched, and the stretching is disproportionate in the macular region where scleral and retinal thinning is maximal. This leads to formation of a focal out-pouching, or staphyloma. As the macular tissues stretch, retinal cells atrophy, causing irreversible visual loss. While visual loss from macular atrophy and choroidal neovascularization are most common in degenerative myopia, patients with this disease are also more prone to retinal detachment and macular hole formation. Although a large population is affected by this disease worldwide, there is currently no effective method to arrest progression and reduce the rate of visual loss.
Refractive errors induced by progressive myopia are readily corrected by spectacles, contact lenses, corneal refractive surgery, or intraocular lenses, these modalities do not prevent visual loss induced by stretching of chorioretinal tissues. Furthermore, current means to treat choroidal neovascularization in degenerative myopia, such as photodynamic therapy, are minimally effective (Blinder, K. J., Blumenkranz, M. S., Bressler, N. M., Bressler, S. B., Donati, G., Lewis, H., Lim, J. I., Menchini, U., Miller, J. W., Mones, J. M., Potter, M. J., Pournaras, C., Reaves, A., Rosenfeld, P., Schachat, A. P., Schmidt-Erfurth, U., Sickenberg, M., Singerman, L. J., Slakter, J., Strong, H. A., Virgili, G. & Williams, G. A. Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia-2-year results of a randomized clinical Trial—VIP report no. 3. Ophthalmology 110, 667-673 (2003)). A role for anti-vascular endothelial growth factor (VEGF) therapy, such as Lucentis®, for treatment of choroidal neovascularization has not yet been established. Various attempts have been made to arrest progression of myopia, including the use of scleroplasty, scleral reinforcement, and even an attempt to polymerize foam around the eye (Avetisov, E. S., Tarutta, E. P., Iomdina, E. N., Vinetskaya, M. I. & Andreyeva, L. D. Nonsurgical and surgical methods of sclera reinforcement in progressive myopia. Acta Ophthalmologica Scandinavica 75, 618-623 (1997); Chua, W. H., Tan, D., Balakrishnan, V. & Chan, Y. H. Progression of childhood myopia following cessation of atropine treatment. Investigative Ophthalmology & Visual Science 46 (2005); Tarutta, Y. P., Iomdina, Y. N., Shamkhalova, E. S., Andreyeva, L. D. & Maximova, M. V. Sclera Fortification In Children At A High-Risk Of Progressive Myopia. Vestnik Oftalmologii 108, 14-17 (1992); Politzer, M. Experiences In Medical-Treatment Of Progressive Myopia. Klinische Monatsblatter Fur Augenheilkunde 171, 616-619 (1977); Belyaev, V. S. & Ilyina, T. S. Late Results Of Scleroplasty In Surgical Treatment Of Progressive Myopia. Eye Ear Nose And Throat Monthly 54, 109-113 (1975); Chauvaud, D., Assouline, M. & Perrenoud, F. Scleral reinforcement. Journal Francais D Ophtalmologie 20, 374-382 (1997); Jacob, J. T., Lin, J. J. & Mikal, S. P. Synthetic scleral reinforcement materials.3. Changes in surface and bulk physical properties. Journal Of Biomedical Materials Research 37, 525-533 (1997); Korobelnik, J. F., D'Hermies, F., Chauvaud, D., Legeais, J. M., Hoang-Xuan, T. & Renard, G. Expanded polytetrafluoroethylene episcleral implants used as encircling scleral buckling—An experimental and histopathological study. Ophthalmic Research 32, 110-117 (2000); Mortemousque, B., Leger, F., Velou, S., Graffan, R., Colin, J. & Korobelnik, J. F. S/e-PTFE episcleral buckling implants: An experimental and histopathologic study. Journal Of Biomedical Materials Research 63, 686-691 (2002); Jacoblabarre, J. T., Assouline, M., Conway, M. D., Thompson, H. W. & McDonald, M. B. Effects Of Scleral Reinforcement On The Elongation Of Growing Cat Eyes. Archives Of Ophthalmology 111, 979-986 (1993)). Largely because these modalities remain unproven in well controlled clinical trials, none has been widely adopted to manage patients with degenerative myopia. Other therapies, such as eye drops (Chua W H, Balakrishnan V, Chan Y H, Tong L, Ling Y, Quah B L, Tan D. Atropine for the treatment of childhood myopia. Ophthalmology. 2006 December; 113(12):2285-91; Siatkowski R M, Cotter S, Miller J M, Scher C A, Crockett R S, Novack G D; US Pirenzepine Study Group.Safety and efficacy of 2% pirenzepine ophthalmic gel in children with myopia: a 1-year, multicenter, double-masked, placebo-controlled parallel study. Arch Ophthalmol. 2004; 122(11):1667-74), eye exercises (Khoo C Y, Chong J, Rajan U. A 3-year study on the effect of RGP contact lenses on myopic children. Singapore Med J 1999; 40:230-7), and contact lens therapy (Shih Y F, Lin L L, Hwang C Y, et al. The effects of qi-qong ocular exercise on accommodation. Clin J Physiol 1995; 38:35-42) have either minimal or no proven efficacy. Were it possible to retard or prevent abnormal axial elongation of the globe in degenerative myopia, visual loss might be prevented.
The excessive axial enlargement of the globe that occurs in degenerative myopia occurs preferentially in the posterior pole in the macula. The causes of scleral thinning and stretching in degenerative myopia are incompletely understood, but reduction of collagen fibril diameter, enhanced turnover of scleral collagen, and alteration of scleral glycosaminoglycans are contributory factors (McBrien, N. A. & Gentle, A. Role of the sclera in the development and pathological complications of myopia. Progress In Retinal And Eye Research 22, 307-338 (2003)). As the mechanical properties of the sclera are altered in myopia, the eye is prone to stretching due to the load effect of intraocular pressure. Sufficiently increasing the tensile strength, or modulus, of the sclera would prevent ocular enlargement and reduce progression of myopia. Such a therapy will be useful not only in patients with incipient degenerative myopia, but also in patients with early onset myopia to prevent progression to higher magnitude refractive errors.
Currently, there are no proven means to prevent the excessive ocular enlargement that occurs in degenerative myopia. Were it possible to retard or prevent ocular enlargement, progression of myopia could be diminished and visual loss prevented at least in part. Were the progressive stretching of the sclera in the macular region to be arrested, retinal stretching or further retinal stretching would not occur, and vision could be preserved. Efforts have been made to support the macular region with an external donor scleral or synthetic polymer band placed around the eye, but this has not been proven to be effective. Artificially increasing the tensile strength or modulus of the sclera itself is a means to prevent ocular enlargement and reduce progression of myopia.
Wollensak and Speorl have reported use of collagen cross-linking agents, including glutaraldehyde, glyceraldehyde, and riboflavin-UVA treatment, to strengthen both human and porcine sclera in vitro (Wollensak, G. & Spoerl, E. Collagen crosslinking of human and porcine sclera. Journal Of Cataract And Refractive Surgery 30, 689-695 (2004)). Glutaraldehyde, glyceraldehyde, and riboflavin-UVA treatments increased Young's modulus by 122%, 34%, and 29% respectively compared to untreated controls. Since they are not light-activated, the authors report that it might be difficult to spatially control the cross linking effects of both glutaraldehyde and glyceraldehyde. Unwanted cross-linking of collagen in vascular and neural structures might have particularly untoward effects. Use of light activated riboflavin would seem preferable in this regard; however, UVA light is potentially cytotoxic and comparable exposures in the cornea to treat keratoconus require 30 minute irradiations (Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006; 17(4):356-60). While cross-linking of scleral stromal components in the posterior pole would increase scleral modulus and potentially arrest myopic progression, there remains a need for a non-toxic cross-linking agent that could be activated using short exposure to a less toxic light source.
U.S. Published Application No. 20050271590, the contents of which are incorporated herein by reference, discloses methods of using crosslinking chemicals to covalently connect scleral collagen and/or other scleral proteins to increase scleral tensile strength or modulus. This approach utilizes chemical crosslinkers, some with undesirable toxicity profiles, by caging the chemicals in photo-labile structures which are disrupted to release the crosslinker chemicals in a controlled manner, thereby limiting the area of exposure and in some instances toxicity effects.
Given the limitations of current therapies for treating keratoconus and myopia, new therapies without such limitations are needed. The present invention fulfills this need.